Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

• Published in: Diabetologia Vol. 54; no. 6; pp. 1407 - 1416
• Main Authors: Lee, A. S., Ghoreishi, M., Cheng, W. K., Chang, T.-Y. E., Zhang, Y. Q., Dutz, J. P.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-06-2011; Springer; Springer Nature B.V
• Subjects: Animals; Antigens; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmune Diseases - physiopathology; Biological and medical sciences; Bone marrow; Bone Marrow Cells - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD40 Antigens - pharmacology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cytokines; Cytokines - metabolism; Cytotoxicity; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Diabetes; Diabetes Mellitus - immunology; Diabetes Mellitus - pathology; Diabetes Mellitus - physiopathology; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Human Physiology; Imidazoles - pharmacology; Interferon-alpha - metabolism; Internal Medicine; Lymphatic system; Lymphocytes; Medical sciences; Medicine; Medicine & Public Health; Membrane Glycoproteins - agonists; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Metabolic Diseases; Mice; Mice, Inbred NOD; Mice, Transgenic; Pathogens; Phosphatase; Quinolines - pharmacology; T cell receptors; Toll-Like Receptor 7 - agonists; Toll-Like Receptor 7 - antagonists & inhibitors; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - physiology; Transgenic animals; Viral infections; Canada; United States > US; CD40 agonist; IFN-α; T cell activation; 8.3 NOD mice; BMDC; CD8; CL097; Autoimmune diabetes; TLR7; IRS661; Endocrinopathy; Autoimmunity; Agonist; Alpha interferon; Diabetes mellitus; Rodentia; Toll like receptor; Vertebrata; Mammalia; Mouse; Animal; T-Lymphocyte
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2083-y

Aims/hypothesis
The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8
+
T cells.
Methods
We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8
+
T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice).
Results
TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes.
Conclusions/interpretation
TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.